Sulfated and unsulfated steroids modulate γ-aminobutyric acid A receptor function through distinct sites
Sulfated and unsulfated neurosteroids such as pregnenolone sulfate, dehydroepiandrosterone sulfate (DHEAS), pregnanolone, and allopregnanolone, modulate ionotropic amino acid neurotransmitter receptors, and may function as endogenous neuromodulators. The γ-aminobutyric acid type A (GABA A) receptor...
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Published in | Brain research Vol. 830; no. 1; pp. 72 - 87 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
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Elsevier B.V
29.05.1999
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Abstract | Sulfated and unsulfated neurosteroids such as pregnenolone sulfate, dehydroepiandrosterone sulfate (DHEAS), pregnanolone, and allopregnanolone, modulate ionotropic amino acid neurotransmitter receptors, and may function as endogenous neuromodulators. The γ-aminobutyric acid type A (GABA
A) receptor exhibits both negative and positive modulation by neurosteroids, but the interaction between negative and positive modulators is not well-understood. For a number of neuroactive steroids, sulfation at C-3 reverses the direction of modulation from positive to negative, suggesting that sulfation could be an important control point for the activity of endogenous neurosteroids. Modulation by endogenous and synthetic steroids of the response to exogenous or synaptically released GABA was examined in primary chick spinal cord and rat hippocampal neurons, and in
Xenopus laevis oocytes expressing α1β2γ2S GABA
A receptors. Inhibitory activity is retained when hemisuccinate is substituted for sulfate at C-3, suggesting that it is the negative charge, rather than the sulfate group, that confers inhibitory efficacy. The interaction between steroid negative and positive modulators is not competitive, indicating that steroid negative and positive modulators act through distinct sites. Some steroids, such as 11-ketopregnenolone sulfate, appear to act at both negative and positive modulatory sites, as indicated by an `off-response' upon washout. A similar off-response is also observed after co-application of the negative modulator DHEAS and the positive modulator allopregnanolone. The observation that simultaneous application of sulfated and unsulfated steroids, such as DHEAS and allopregnanolone, act at distinct sites implies that steroid negative and positive modulators can act independently or coordinately to regulate GABA-mediated inhibition in the central nervous system. |
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AbstractList | Sulfated and unsulfated neurosteroids such as pregnenolone sulfate, dehydroepiandrosterone sulfate (DHEAS), pregnanolone, and allopregnanolone, modulate ionotropic amino acid neurotransmitter receptors, and may function as endogenous neuromodulators. The γ-aminobutyric acid type A (GABA
A) receptor exhibits both negative and positive modulation by neurosteroids, but the interaction between negative and positive modulators is not well-understood. For a number of neuroactive steroids, sulfation at C-3 reverses the direction of modulation from positive to negative, suggesting that sulfation could be an important control point for the activity of endogenous neurosteroids. Modulation by endogenous and synthetic steroids of the response to exogenous or synaptically released GABA was examined in primary chick spinal cord and rat hippocampal neurons, and in
Xenopus laevis oocytes expressing α1β2γ2S GABA
A receptors. Inhibitory activity is retained when hemisuccinate is substituted for sulfate at C-3, suggesting that it is the negative charge, rather than the sulfate group, that confers inhibitory efficacy. The interaction between steroid negative and positive modulators is not competitive, indicating that steroid negative and positive modulators act through distinct sites. Some steroids, such as 11-ketopregnenolone sulfate, appear to act at both negative and positive modulatory sites, as indicated by an `off-response' upon washout. A similar off-response is also observed after co-application of the negative modulator DHEAS and the positive modulator allopregnanolone. The observation that simultaneous application of sulfated and unsulfated steroids, such as DHEAS and allopregnanolone, act at distinct sites implies that steroid negative and positive modulators can act independently or coordinately to regulate GABA-mediated inhibition in the central nervous system. |
Author | Gibbs, Terrell T. Park-Chung, Mijeong Farb, David H. Malayev, Andrew Purdy, Robert H. |
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Keywords | Neurosteroid Dehydroepiandrosterone sulfate GABA A receptor Pregnanolone Allopregnanolone |
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SubjectTerms | Allopregnanolone Dehydroepiandrosterone sulfate GABA A receptor Neurosteroid Pregnanolone |
Title | Sulfated and unsulfated steroids modulate γ-aminobutyric acid A receptor function through distinct sites |
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